Ekaterina Elts

Insights into Pharmaceutical Nanocrystal Dissolution: A Molecular Dynamics Simulation Study on Aspirin

The presented molecular dynamics simulations are the first simulations to reveal dynamic dissolution of a pharmaceutical crystal in its experimentally determined shape. Continuous dissolution at constant undersaturation of the surrounding medium is ensured by introducing a plane of sticky dummy atoms into the water slab. These atoms have a strong interaction potential with dissolved aspirin molecules, but interactions with water are excluded from the calculations. Thus, the number of aspirin molecules diffusing freely in solution is kept at a low value and continuous dissolution of the aspirin crystal is monitored. Further insight into face-specific dissolution is drawn. The dissolution mechanism of receding edges is found for the (001) plane. These findings are in good agreement with experimental results. While the proposed dissolution mechanism for the (100) plane is terrace sinking on a rough surface, no pronounced dissolution of the perfectly flat face is seen in the present work. Molecular simulations of pharmaceuticals in their experimentally obtained structure therefore have shown to be especially suited for the investigation of dissolving faces, where the edges have a pronounced effect. In contrast to previous studies a propagation of the dissolution front into the crystal face is reported, and the crystal bulk is stable over the whole simulation time of 150 ns.

Simulating preferential sorption of tartrate on prismatic calcite surfaces

Understanding the influence of additives on crystal growth is required to engineer the crystal properties according to their functional applications. In this work, the sorption behavior of tartrate on calcite surfaces is investigated employing molecular dynamics simulations to understand additive-mediated crystal growth. The free energy landscapes for the sorption of tartrate are calculated using metadynamics. The adsorption binding energies of favorable conformations, orientations and positions of tartrate near the (104) and (1−10) calcite surfaces are determined. The obtained results provide a molecular-level explanation of the experimentally observed tartrate-stabilized exposure of prismatic {1−10} faces during calcite growth. The simulations show that tartrate preferentially adsorb directly to the (1−10) calcite surface, whereas tartrate is more loosely adsorbed on the (104) surface, mainly by solvent-mediated binding. The (1−10) geometry of calcite surface sites closely matches the structure of tartrate, with a specific role of carboxylate and hydroxyl groups in recognizing the calcium and carbonate ions, respectively. Two stable adsorption configurations are identified for the (1−10) face: (1) adsorbed tartrate with the effect of surface-induced conformational change and (2) incorporated tartrate into the surface by fitting one of the carboxylate groups into lattice position normally occupied by carbonate ions and additionally stabilized by binding of both hydroxyl groups to neighboring carbonate ions. The results indicate that surface energetics, structural matching and adsorbed water layer play a major role in the strength of the interactions and hence in the expression of calcite morphology. Preferential adsorption of tartrate on {1−10} surfaces could stabilize these otherwise fast-growing faces and thus inhibit crystal growth in {1−10} directions.

Data Filtering for Effective Analysis of Crystal–Solution Interface Molecular Dynamics Simulations

Analysis of processes occurring at the solid-solution interface during crystal growth and dissolution simulations requires an effective way to detect rare, uncorrelated transitions from the liquid to the solid state or vice versa. Because of the oscillatory behavior of molecules, this is not a trivial problem. Usually, to take the thermal vibration and rotational flexibility of the molecules into account, the data (e.g., orientation, center of mass position) needed to determine the molecular state are averaged over some time interval. Then they are evaluated using some order parameters to classify the individual molecules as being either crystalline or in solution. In this case, the results can be very sensitive to the time interval, which is mostly chosen in some heuristic way. To suppress the problem of fast non-Markovian dynamics and to make the identification of the molecular state more reliable and robust, the application of a Kalman filter, optionally combined with a hysteretic approach, is proposed in this contribution. A scheme to estimate the filter parameters is introduced. To demonstrate the approach, simple and widely used order parameters based on the structural features of molecules are taken. The obtained results are clearly superior to those based on the data averaging technique and are important for the effective transition rates calculation as well as for the general analysis of the time evolution of interfaces.

Deep eutectic solvent formation: a structural view using molecular dynamics simulations with classical force fields

ABSTRACT Deep eutectic solvents (DES) have gained a reputation as inexpensive and easy to handle ionic liquid analogues. This work employs molecular dynamics (MD) to simulate a variety of DES. The hydrogen bond acceptor (HBA) choline chloride was paired with the hydrogen bond donors (HBD) glycerol, 1,4-butanediol, and levulinic acid. Levulinic acid was also paired with the zwitterionic HBA betaine. In order to evaluate the reliability of data MD simulations can provide for DES, two force fields were compared: the Merck Molecular Force Field and the General Amber Force Field with two different sets of partial charges for the latter. The force fields were evaluated by comparing available experimental thermodynamic and transport properties against simulated values. Structural analysis was performed on the eutectic systems and compared to non-eutectic compositions. All force fields could be validated against certain experimental properties, but performance varied depending on the system and property in question. While extensive hydrogen bonding was found for all systems, details about the contribution of individual groups strongly varied among force fields. Interaction potentials revealed that HBA–HBA interactions weaken linearly with increasing HBD ratio, while HBD–HBD interactions grew disproportionally in magnitude, which might hint at the eutectic composition of a system.

Grid-Supported Simulation of Vapour-Liquid Equilibria with GridSFEA

In order to benefit from grid computing, software applications in CSE often need to be substantially modified or rewritten to a large extent. To reduce the required grid know-how and effort the computational scientist (end user and software developer) needs for this task, we developed a framework for engineering simulations in grid environments (GridSFEA). This paper presents two novel features of GridSFEA: the integrated support for parameter investigations and the controlled execution of long-running simulations in grids. They allow the grid enabling of CSE applications with minimal or even without changes of their source code. Furthermore, the overhead for working in grid environments introduced by our approach, compared to working on classical HPC platforms, is very low. We provide two examples of using GridSFEA for performing vapour-liquid equilibria (VLE) simulations using Molecular Dynamics and Monte Carlo methods. To develop VLE models, parameter investigations are carried out. Large VLE scenarios are computed over a long time, to create test cases for the development of HPC software.

Multiscale modeling of aspirin dissolution: from molecular resolution to experimental scales of time and size

This paper presents a multiscale modeling approach for the dissolution of aspirin. Recent advances in multiscale simulation techniques are reviewed, and the need to derive absolute rate constants in order to predict dynamic properties during crystal growth or dissolution is highlighted. Absolute face-specific rate constants obtained in our recent study on molecular dynamics and kinetic Monte Carlo simulations are incorporated in a simulation based on the equations of classical mass transfer. As experimental reference, a Jamin-type interferometer is used to monitor the face displacement velocity and concentration gradient within the bulk liquid. An experimental setup that is consistent with the simulation settings to monitor crystal dissolution, based on a non-saturated resultant solution, is chosen. The face displacement velocity of the investigated (001) face as well as the final average concentration of aspirin in water are found to be in good agreement with the experimental data. The dissolution mechanism of aspirin is found to be diffusion-controlled in both the simulation and experiment. Furthermore, a method to predict all experimental and literature values used in the study, such as diffusion coefficients and solubilities, is presented.

Grid Workflows for Molecular Simulations in Chemical Industry

Today, molecular simulation is a very important technique not only for fundamental research in the science, but also for chemical engineering and chemical industry. Sometimes it is the most efficient or even the only way to obtain useful estimates for parameters and behaviour needed to do traditional chemical engineering process development and design. In order to elaborate appropriate molecular models, one has to carry out extensive parameter studies for workflows, consisting of multiple different operations. This paper discusses a number of aspects of using grid computing methods in support of molecular simulations, with examples drawn from the vapour-liquid equilibria simulations, concerns the GridSFEA software tools development, designed to facilitate the execution, monitoring, and management of such simulations in computational grids, and presents an integrated scientific workflow solution aiming at automating parameter studies for the fast elaboration of molecular models.